November 6, 2008

As a college athlete in an extremely physically demanding sport, a great deal of my life centers around exercise. I have always known that exercise is an activity which promotes physical health and for that reason alone, was enough motivation to partake in it. Who in their right mind does not want to ward of diseases like diabetes or maintain strong and healthy heart functions? With a formerly weak immune system and terrible asthma, exercise has improved the quality of my life in ways that I could not have imagined.

This lack of imagination has once again gotten the better of me. It turns out there are surprising psychological benefits of exercise. A study performed at Duke University which studied the levels of depression among subjects divided into three specific treatment groups. These included a group being treated with SSRI’s (Serotonin Specific Reuptake Inhibitors), one with an exercise regime and the final one with a combination of both SSRI’s and exercise. Not surprisingly, all formerly depressed patients showed a significant decrease in depression levels at the end of the study, with two thirds of the group having eradicated it all together. What is surprising however, is the fact that six months after the conclusion of the study, participants in the exercise only group were in better shape, psychologically, than members of either of the other groups. Specifically, the were more likely to have experienced full or partial recovery, even when compared to the exercise plus medication groups.

As a rower, I am intimately familiar with one of the brain’s responses under prolonged physical exertion. The release of endorphin neurotransmitters under such conditions lessen pain and boost mood in what is often called a “runner’s high.” This “high” has very short term effects however, ending shortly after or even during the workout (Myers, 2007). While the sense of accomplishment from achieving a physical goal may also stimulate endorphin release, even this fades within a relatively short time span. This begs the question of how exercise actually affects us in the long run. Does habitual exercise physiologically remap our brains in some way that we naturally maintain higher levels of serotonin or have neurons that are more receptive to these pleasurable neurotransmitters? Or maybe positive changes in one’s self-image through weight loss or an increase in one’s perceived health eventually leads to a physiological change in the brain. If this is the case, then just how necessary are SSRI’s like Prozac and Zoloft, especially given a slew of negative and potentially dangerous side effects that can arise from frequent use?

November 6, 2007

Girls stress and get depressed. Boys can’t control themselves. And it’s not their fault.

In a study conducted by Dr. Espen Walderhaug and his colleagues, women and men are found to behave differently when serotonin levels were lowered. When given a treatment of acute tryptophan depletion, men became more impulsive and displayed such effects usually demonstrated in impulse control disorders and alcoholism. Surprisingly, they did not appear to demonstrate mood changes. Women, however, reported a worsening of their mood, and became more cautious. Both responses are characteristic of and associated with MDD (Major depressive disorder, commonly known as depression).

What the researchers also discovered was that the women’s moods were influenced by variation in the promoter region of the serotonin transporter gene (5-HTTLPR). The 5-HTTLPR gene is an important part of the serotonin system, which helps to regulate mood in men and women. It has been shown to control overall response to SSRIs in patients with MDD.

So if men and women have the same brain areas for our serotonergic systems, what makes the result so drastic? Dr. Walderhaug hypothesizes that men and women may use serotonin differently. He hopes the study’s findings will help us understand why women risk a higher chance of mood and anxiety disorders while men have a higher probability of abusing alcohol and suffering from impulse control disorders.

October 16, 2007

In recent years, society has seen an incredible leap in science and medicine. We’ve evolved from treating wounds with plants and locking up the mentally unstable to curing everything with a pill. While in many cases, these medical advances are incredibly beneficial, sometimes pills seem to be too readily chosen as the answer for every problem; a recent study published in the New York Times discusses alternative therapies for depressed adolescents other than simply drugging the patient up and leaving him be.
Researchers in the article Talk Therapy for Depressed Youth tested 654 clinically depressed twelve – seventeen year olds for a year and examined how different anti-depression mechanisms worked. Patients were either given Prozac, placebo pills, cognitive behavioral therapy (“talk therapy”), or a combination of Prozac and talk therapy. Those taking Prozac or the combination of Prozac and talk therapy were deemed better within twelve weeks, while talk therapy alone was just as ineffective as placebo pills. After nine months, most of the group had shaken off their depression, but those who hadn’t received talk therapy with their Prozac reported sudden suicidal feelings. The mixture of the healing drug with the healing conversations proved to better the person best overall.

October 1, 2007

In a world where illnesses once thought debilitating have become more treatable than ever, the question of whether or not a treatment is available for an affliction like depression has become almost obsolete. The difficulty has shifted to the issue of which drug is best for which patient, and how a balance may be found between treatment and side effects.
Recent government-funded studies, reported in the New York Times, have shown that Celexa, an anti-depressant drug belonging to the class of selective serotonin reuptake inhibitors (SSRIs) may cause patients to experience suicidal thoughts. Interestingly, those same suicidal thoughts tended to be found in patients who did not actually attempt suicide, while it has been noted that the one patient in the study that did actually attempt suicide vehemently denied any thoughts of suicide.

Unsurprisingly, the physiology of the connection may be traced to the brain. Throughout the course of the study, two out of the sixty-eight genetic markers studied were noteworthy, as 36 percent of the subjects in possession of the markers experienced suicidal thoughts after taking Celexa. The markers coded for an amino acid called glutamate, which, aside from working as a natural antidepressant by activating neurons, is involved with learning and memory in the brain. Although the results of the tests were inconclusive, they raise the serious question of how treatment can be achieved without a flurry of undesirable (and sometimes dangerous) side effects. It is also remarkable to think that, with time and more research, a genetic test may be developed that is capable of pinpointing exactly which depression treatment is best for each patient.

[Editor’s note: Interested readers may also want to look at this post about why the added caution around SSRIs also causes problems.]

Source:

Carey, Benedict. (2007 September 28). Genes Tied to Bad Reactions to Antidepressant Drug. New York Times. Retrieved September 30, 2007, from http://www.nytimes.com.

September 19, 2007

What constitutes the main effect of a drug, and what constitutes the side effect? Aspirin relieves headaches, but also thins your blood as a side effect. Unless you are taking aspirin to prevent a heart attack, and then it is the other way around. With psychoactive drugs, that target one or more neurotransmitters, it can be even harder to sort out. It takes complicated research to figure out the complicated effects of many psychoactive medications.

Here is a story about a complicated study that looks at one effect of one well-known drug, bupropion, which is marketed as both Zyban and as Wellbutrin. The patients studied were all ADHD patients, boys and girls, ranging from 9 to 18 years old. Half were given a daily dose of bupropion, and half were given a placebo, and then they were followed for about a year.

Wellbutrin is marketed as an antidepressant. Why give people with ADHD an antidepressant? At first glance, this seems odd at best. Most modern antidepressants, like Prozac, Paxil, and Zoloft are SSRIs (selective serotonin reuptake inhibitors). They primarily target the neurotransmitter serotonin, which helps to regulate mood, among many other functions. Wellbutrin, by contrast, targets dopamine primarily, as well as norepinephrine and serotonin. All three play a role in mood regulation, so Wellbutrin provides an alternative when SSRIs are not very effective. Norepinephrine and serotonin may be at least as important in depression, but it is the dopamine that we focus on here.

“We now know that by increasing the levels of extracellular dopamine, you can activate these motivational circuits and make the tasks that children are performing seem much more exciting. By raising that level of interest, you can significantly increase the ability of the child to focus on the task.”

In other words, a controlled rise in dopamine levels improves motivation and focus in kids who have trouble with both.

Compared to cocaine or amphetamines, which also boost dopamine, ritalin’s action is much slower (when taken in pill form). That probably explains why cocaine and amphetamines are highly addictive, but Ritalin is not. A slow boost in dopamine may also explain why bupropian/Wellbutrin is effective as an ADHD treatment. It is working in a similar fashion to Ritalin, though by a different chemical mechanism.

So one drug, bupropion, is useful in treating both depression and ADHD. But what does this have to do with smoking?

Zyban, which is exactly the same drug as Wellbutrin, is marketed as a helper in stopping smoking. As far as I know, there is no definitive research to show how it works. But I will speculate that since nicotine in cigarette smoke provides a dopamine boost, nicotine withdrawal involves the body expecting that dopamine boost and not getting it. Zyban may relieve that craving by raising dopamine levels, although more slowly and not as much as nicotine does.

Now, back to the complicated study. If bupropion (as Zyban) helps people quit smoking, should it also help adolescents avoid smoking in the first place? Dr. Michael C. Monuteaux and his colleagues (reported in the Journal of Clinical Psychiatry, July 2007) tested this by experimentally manipulating whether patients got bupropion or a placebo. They could not, of course, manipulate whether the patients had ADHD. They all did. Nor did they control whether they were taking Ritalin or another stimulant-based drug, but they carefully tracked this. They had patients of different ages, but the results cited in the news story do not point to any age-related differences. They checked on the outcome variable, whether or not the patients smoked, by looking for a nicotine by-product in their urine.

The result must have been disappointing: The patients in the bupropion group were actually more likely to start smoking than the patients in the placebo group. The drug that works well for stopping smoking was no good at all in preventing these patients from starting to smoke. I don’t know why that was any more than Dr. Monuteaux. I can speculate that maybe starting and stopping reflect different underlying neural mechanisms.

There was another result. Unexpectedly, the patients who were taking stimulant-based drugs, like Ritalin or a generic equivalent, were less likely to smoke. So now Ritalin may turn out to have an unexpected, but beneficial side-effect. As usual, we need more research.

One question lingers with me most of all: Why are kids with an ADHD diagnosis more likely to take up smoking in the first place. Some researchers have suggested that this is an attempt to self-medicate. That raises the interesting possibility that understanding more about nicotine addiction may help us to understand more about ADHD as well. But I promise it will still be complicated.

August 28, 2007

My favorite obsessive compulsive detective, Monk, may never clear up the mystery of who killed his beloved wife, but scientists are closer to clearing up the mystery of why Monk is obsessive compulsive. The new discovery is that mice who are missing a protein called SAPAP3 act like they, too, have OCD (obsessive compulsive disorder). They do not boil their toothbrushes before using them or wash their hands 100 times, of course, but then the compulsive behaviors of humans vary quite a bit from individual to individual anyway. Just like humans, these OCD mice exhibit what looks like an unhealthy obsession with cleanliness. They lick and groom themselves to the point of destroying their fur, and damaging their skin. They do this even when they should be sleeping. They do not solve mysteries, so far as we know.

How is it that these mice were missing that particular protein? Well, these are very special mice. They have been genetically engineered. Specifically, the gene that codes for SAPAP3 has been removed, or “knocked-out” of their DNA. We can call them SAPAP3 knock-out mice. And they were created for that best of scientific reasons: the researchers just wanted to see what would happen if you took that gene out.

This story should raise a lot of questions in the minds of readers who do not have a lot of background in genes and behavior.

Q: What does knocking out a gene affect a particular protein?

A: We think of genes as just being a kind of code, that passes on information about traits from parents to children. But in fact, genes are much more than that. They are protein factories. What you inherited from your parents are 23,299 little protein-building machines. It is the proteins they build that do the work of every cell in your body. Different kinds of cells get different proteins, because different genes are switched on and off for different cells. So these SAPAP3 knock-out mice have had the genes for that one protein effectively turned off for every cell.

Q: Why does a protein affect grooming behavior?

A: Like any behavior, grooming involves a great many neurons (nerve cells). Neurons “talk” to each other by means of chemicals called neurotransmitters. One neuron releases a neurotransmitter, and the next one picks it up. SAPAP3 plays a role in the transmission of the neurotransmitter glutamate. What brain circuitry is being messed up by the lack of SAPAP3 is not clear. Since glutamate is an excitatory neurotransmitter used all over the nervous system, there are many possibilities. So we know that the lack of SAPAP3 is interfering with the normal function of the nervous system, but we do not know exactly what it does to increase grooming.

I should also point out that the neurotransmitter more often associated with OCD and other anxiety related disorders is serotonin.

Q: Is there anything that can be done for these poor mice?

A: Yes! As it turns out, they respond to fluoxetine (prozac). This drug, which is also used to treat OCD in humans, significantly reduced their grooming behavior. This drug is a serotonin specific reuptake inhibitor (SSRI), which only makes the glutamate connection more puzzling.

Q: Is Adrian Monk an SAPAP3 knock-out human?

A: Not in the same way as the mice. He has not been genetically engineered. But it is possible that natural genetic variations among humans contribute to OCD. It is also possible that lower production of this protein is involved in OCD in humans, but we will need new studies to look at this.

Something to keep in mind whenever you read a story about a gene that has been identified with this or that disorder: Just because the gene plays a role in some individuals does not mean that the same gene plays the same role in everyone. There might be multiple genes involved. There might be many pathways to the same illness. In fact, it is an entirely different gene linked to OCD that most researchers have been focused on the past several years.

One thing is clearly different between mice and men (at least OCD mice and men): For these mice this is purely genetic. In humans, it may be a mix of genes and experience. In some humans, that experience may be a strep throat, which then triggers an autoimmune response. Family dynamics and life stress certainly play a role in the ups and downs of OCD, but probably not in creating it.

Finally, it is worth pointing out that the mice’s behavior might not really be analogous to OCD in humans. OCD is one kind of anxiety disorder, but not the only kind. Self-grooming is a way to calm anxiety. Then again, so is touching every parking meter on the sidewalk as you go by, if you are Adrian Monk.